FR2839716A1 - Process for enabling nucleophilic substitution reactions, uses an ionic liquid or fused salt as a fluorinating medium - Google Patents

Abstract

Process for enabling SN2 and SNAr type nucleophilic substitution reactions, uses a composition comprising an ionic liquid or fused salt as a fluorinating medium for the synthesis of fluoride derivatives. Process for enabling SN2 and SNAr type nucleophilic substitution reactions, uses a composition comprising an ionic liquid or fused salt of formula (G) as a fluorinating medium for the synthesis of fluoride derivatives. R1, R2, R3, R4 = monovalent hydrocarbyl radicals; n = 0 or 1; A = a metalloid of group VB; and E = a divalent group attached to a double bond which is conjugated to the E = A double bond and/or another metalloid attached to a doublet which is conjugated directly or indirectly with the E = A double bond. Independent claims are also included for: (1) use of the compositions; and (2) the process of nucleophilic substitution.

Description

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Use of a composition of ionic nature as a substitution reagent, composition constituting a fluorination reagent and process using it
The subject of the present invention is the use of compounds of ionic nature as a reaction medium or as a solvent in nucleophilic substitution type reactions. It relates more particularly to obtaining fluorinated derivatives by replacing a leaving group, in particular halogen or pseudohalogen, with a fluorine.

 This substitution reaction is a substitution reaction called aromatic nucleophilic substitution (SNAr) when the substitution takes place on an aromatic nucleus and nucleophilic substitution of order 2 (SN2) when the substitution takes place on a chain of aliphatic nature and when the kinetics is of order 2, ie the rate depends on both the concentration of substituents and substrates.

 One of the interesting aspects of the present invention is the improvement of aromatic nucleophilic substitution reactions known as Meisenheimer.

 It may be interesting to recall here some basic data of Meisenheimer reactions.

 The aromatic nucleophilic substitution reactions generally involve the following reaction scheme: - attack of a nucleophilic agent at an aromatic substrate with creation of a bond between said nucleophilic agent and said substrate, at a carbon bearing a leaving group, so as to form an intermediate compound, said Meisenheimer intermediate (when the nucleophile is an anion) or equivalent and - departure from said leaving group.

 Examples of SNAr intermediates are: #R represents any radicals; #n the number of substituent radicals; #GEA represents an Electro-Attractor Group; #gp represents a leaving group, or rather the leaving group considered.

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Intermediate Example of Equivalent Intermediate Example
Meisenheimer where Nu to that of Meisenheimer where NuH is is a neutral nucleophile anionic nucleophile
This type of reaction is particularly advantageous for obtaining halogenated aromatic derivatives and especially used for carrying out exchanges between fluorine on the one hand, and halogen (s) of higher rank or pseudo-halogen (s) on an aromatic substrate of other share.

 The leaving group may thus be a nitro group, advantageously a pseudo-halogen or preferably a halogen atom, especially of atomic number greater than that of fluorine.

 The term "pseudo-halogen" is intended to denote a group whose start leads to a chalcogenous anion, most often oxygenated, the anionic charge being carried by the chalcogen atom and whose acidity is at least equal to that of the acid. acetic acid, advantageously to the second acidity of sulfuric acid and preferably that of trifluoroacetic acid. To be on the acidity scale, reference should be made to pKa for medium to high acidities from carboxylic acids to trifluoroacetic acid and to be on the Hammett constant scale from trifluoroacetic acid, see the acidity scale given in the present application.

 By way of illustration of this type of pseudo-halogen, mention may be made in particular of sulfinic and sulphonic acids, perhalogenated on the sulfur-bearing carbon as well as the perfluorinated carboxylic acids in a of the carboxylic function.

 When the leaving group is a nitro group, the latter is generally replaced by a chlorine or fluorine atom. However, most of these reagents need to operate at very high temperatures and the mechanism does not always prove to be a nucleophilic substitution. Moreover, the departure of the nitro group leads to the formation of oxygenated and halogenated nitrogen derivatives particularly aggressive with respect to the substrate, or explosive.

 As regards the variant involving the substitution of a halogen atom present on an aromatic ring with another halogen atom, it generally requires at least partial deactivation of said nucleus. For this purpose, the aryl radical to be converted is preferably depleted of electrons and has a density

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 at most equal to that of benzene, at most close to that of a chlorobenzene, preferably a dichlorobenzene.

 This depletion may be due to the presence in the aromatic ring of a heteroatom such as, for example, in pyridine, and in quinoline (the depletion in this case involves a 6-membered ring). In this particular case, the depletion is large enough that the substitution reaction is very easy and does not require any particular side activation.

The depletion of electrons can also be induced by electron-withdrawing substituents present on this aromatic ring. These substituents are preferably chosen from inductive groups or by mesomeric effect as defined in the reference book in organic chemistry "Advanced Organic Chemistry" by MJ MARCH, 3rd edition, publisher Willey, 1985 (see in particular pages 17 and 238). By way of illustration of these electron-withdrawing groups, there may be mentioned in particular NO 2, quaternary ammonium, Rf and especially CF 3, CHO, CN, COY groups with Y possibly being a chlorine, bromine, fluorine or an alkyloxyl group.

 The SNAr halogen-halogen exchange reactions mentioned above are in fact the main synthetic route for accessing aromatic fluorinated derivatives.

 Thus, one of the most widely used techniques for producing a fluorinated derivative is to react a halogenated aromatic derivative, generally chlorinated, to exchange the halogen (s) with one or more fluorine (s). mineral origin. In general, an alkali metal fluoride, most often of a high atomic weight, such as, for example, sodium and especially potassium fluoride, cesium fluoride and / or rubidium fluoride is used. It is also possible to use onium fluorides.

 In general, the fluoride used is potassium fluoride which constitutes a satisfactory economic compromise.

 Under these conditions, many processes such as for example those described in the French certificate of addition N 2 353 516 and in the article Chem. Ind.

(1978) -56 have been proposed and implemented industrially to obtain aryl fluorides aryl on which are grafted electron-withdrawing groups or aryls naturally poor in electrons, such as pyridine nuclei.

 However, except in the case where the substrate is particularly suitable for this type of synthesis, this technique has drawbacks, the main ones are those which will be analyzed below.

 The reaction is slow and requires, because of a long residence time, large investments. This technique, as already mentioned,

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 especially for the treatment of nuclei with low electron content, is generally used at high temperatures of up to around 250 ° C, or even 300 ° C, ie in the zone where the most stable organic solvents begin to occur. break down.

 Yields remain relatively poor unless particularly expensive reagents such as alkali metal fluorides with atomic weights greater than potassium are used.

 Finally, given the price of these alkali metals, their industrial use is justifiable only for products with high added value and when the improvement in yield and kinetics justifies it, which is rarely the case.

 To solve or to overcome these difficulties, many improvements have been proposed. Thus, new catalysts are proposed, in particular tetradialcoylaminophosphonium, and in particular those described in the patent applications filed in the name of the German company Hoechst and its epigones Clariant and Aventis (for example USP 6,114,589, 6,103,659; in patent applications filed on behalf of Albemarle.

 These new catalysts have certainly some advantages over the usual catalysts but do not bring benefits in proportion to their prices and their complexities.

 Therefore, one of the aims of the present invention is to provide reagents and operating conditions that allow a significant improvement in the kinetics of SNAr reactions.

 Another object of the present invention is to provide reagents and to give operating conditions which notably allow improved kinetics of SNAr reactions even when the seat nucleus of said SNAr is only weakly depleted of electrons.

 Another object of the present invention is to provide reaction media for nucleophilic substitution which allow improved solubility of ionic nucleophiles.

 Another object of the present invention is to provide reaction media for nucleophilic substitution which have a high decomposition temperature, at least 150 C, preferably 200 C, and even 250 C.

Another object of the present invention is to provide reaction media for nucleophilic substitution which make it possible to obtain good yields without it being necessary to go much beyond 200 ° C. for SNAr on Ar - = - whose Ar is a phenyl of which the sum of the Hammett #p constants of its substituents does not exceed 0.5.

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 Another aspect of the invention is to facilitate so-called nucleophilic substitution reactions, especially those considered as nucleophilic substitutions of order 2.

The important problems of this type of reaction is well exemplified by those relating to the exchange reactions between halogen and fluorine, since the aliphatic carbon considered has another electro-attracting substitute inducing effect and / or likely to form a leaving group . In particular, mention may be made of the exchange between fluorine and halogens, the halogen being carried by a carbon which also bears # or at least one other halogen, # or a radical connected to said carbon by a chalcogen; # be an aromatic; # or more than one of the above substituents;
The problem is charged when the carbon comprises, in addition to halogen, or halogens, to exchange, an atom or an electron-withdrawing group, in particular by inductive effect.

 The following explanations are aimed mainly at chlorine-fluorine exchanges on substrates carrying polyhalogenated carbons, generally di- or poly-chlorinated.

 Fluorinated compounds are generally difficult to access. The reactivity of the fluorine is such that it is difficult or impossible to directly obtain the fluorinated derivatives.

 One of the most widely used techniques for producing the fluorinated derivative is to react a halogenated derivative, generally chlorinated, to exchange the halogen with a mineral fluorine, generally an alkali metal fluoride, generally of high atomic weight.

 In general, the fluoride used is potassium fluoride which constitutes a satisfactory economic compromise.

 Except in cases where the substrate is particularly suitable for this type of synthesis, this technique has drawbacks, the main ones are those which will be analyzed below.

 The reaction requires reagents such as alkali metal fluorides such as potassium fluoride which are made relatively expensive by the specifications they must meet to be suitable for this type of synthesis, they must be very pure, dry and in physical form. adapted, usually in atomized form.

 In addition, this reaction does not work for a whole class of products, in particular those relating to the halophoric carbon (that is to say the carbon carrying the halogen or halogens intended to be exchanged with fluorine).

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 Reagents such as liquid hydrofluoric acid or diluted by aprotic dipolar solvents are also used. However, hydrofluoric acid is a too powerful reagent and often leads to unwanted polymerization reactions or tars.

 In this case, and especially in the case where it is desired fluorinated derivatives on a carbon of alkyl type (including aralkyl) depleted in electron by the presence of groups of electro-attractor type, the skilled person is in front an alternative whose terms are hardly encouraging; or very hard conditions are chosen and tar is obtained mainly, or it is placed under mild reaction conditions and the substrate is unchanged in the best case. Finally, it should be pointed out that some authors have proposed to carry out exchanges using hydrofluoric acid salts as reagent in the presence of heavy elements, in particular in the form of mineral cations (in the present description, the elements transition elements, the elements of columns IIIB, IVB, VB when they belong to periods greater than the third), in the form of oxides or fluorides. The elements used include antimony and heavy metals such as silver or quicksilver (mercury).

 Another problem lies in the selectivity of the reaction: when there are several halogens to be exchanged on the same carbon, it is often difficult to exchange only a part of it.

 This is why another object of the present invention is to provide a process which is capable of carrying out the exchange between, on the one hand, heavy halogens such as chlorine and, on the other hand, fluorine, by significantly improving the specificity of the reaction.

Another object of the present invention is to provide a process which is capable of carrying out the exchange between on the one hand heavy halogens such as chlorine and on the other hand fluorine by using mild reaction conditions.

 Another object of the present invention is to provide a method which makes it possible to use a source of fluoride whose morphology is less critical.

 Another object of the present invention is to provide a process which allows only one halogen atom (in particular chlorine) to be exchanged over two (in particular two chlorines) or three possible (in particular three chlorines).

 Another object of the present invention is to provide a method that allows only two of three possible halogen atoms to be exchanged.

 Another object of the present invention is to provide a process which, on the same sp3 carbon, makes it possible to exchange only one halogen atom (in particular

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 chlorine) in two (in particular two chlorine) or in three possible (in particular three chlorines).

 Another object of the present invention is to provide a process which, on the same sp3 carbon, makes it possible to exchange only two halogen atoms out of three possible.

 Another object of the present invention is to provide a method that allows the exchange of molecules or atoms only to the extent that it allows to obtain carbon atoms that carry only a fluorine atom concomitantly with one or two other halogens distinct from fluorine.

 Another object of the present invention is to provide a method which allows the exchange of molecules or atoms only to the extent that it makes it possible to obtain carbon atoms which carry only two fluorine atoms concomitantly with a another halogen distinct from fluorine.

 Another object of the present invention is to provide a method which makes it possible to avoid the use of a large quantity of metals deemed expensive or toxic such as mercury and / or silver.

 Another object of the present invention is to provide a process which makes it possible to reduce the quantities of heavy metals, in particular known to be expensive or toxic, such as mercury and / or silver, so that the molar ratio between the metal and the substrate of which the halogen atoms are to be exchanged, is at a value at most equal to 0.5, advantageously to 0.2, preferably to 0.1.

 Another object of the present invention is to provide a process which makes it possible to completely avoid the use of heavy metals, in particular known to be expensive or toxic, such as mercury and / or silver, so as not to add to the reaction mixture any elements mentioned above; in other words that the concentrations in each of said metals do not exceed the values of 10-3 M; advantageously 10 -4 M, preferably 10-5 M.

 More generally, the present invention aims at performing nucleophilic substitution reactions, in particular aromatic nucleophilic substitution and / or nucleophilic substitution of order 2 to perform the reaction with relatively weak nucleophiles.

 Another object of the present invention is to provide a technique which makes it possible to perform a nucleophilic substitution reaction with neutral or anionic nucleophiles whose associated acid has a pKa of at most 5, preferably at most 4 , said pKa being measured in aqueous phase.

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 Another object of the present invention is to provide a process which makes it possible to carry out a reaction of SNAr and / or type SN2 type which makes it possible to replace with fluorine a halogen heavier than fluorine.

 Another object of the present invention is to provide a method which allows the replacement of a pseudo-halogen with a fluorine.

 Another object of the present invention is to provide a method for carrying out the chlorine-fluorine exchange on an aliphatic atom (that is to say sp3 hybridization) carrier of at least one other halogen heavier than the fluoride to exchange with fluoride.

où R1, R2, R3, et R4, identiques ou différents, sont choisis parmi les radicaux hydrocarbonés monovalents ; où n est choisi parmi les valeurs zéro et un ; où A est un atome métalloïde de la colonne VB (colonne de l'azote) (la classification périodique des éléments utilisée dans la présente demande est celle du supplément au Bulletin de la Société Chimique de France, janvier 1966, n 1) ; où E est un groupe divalent porteur d'au moins une double liaison conjuguée avec la double liaison E=A et/ou d'un autre atome métalloïde porteur d'au moins un doublet, lequel est conjugué directement ou indirectement avec la double liaison E=A, avantageusement d'un métalloïde de la colonne VB dont le doublet est conjugué directement ou indirectement avec la double liaison E=A. These and other objects which will appear later are achieved by means of a reaction medium comprising at least one ionic compound whose cation is of general formula G:

where R1, R2, R3, and R4, which are identical or different, are chosen from monovalent hydrocarbon radicals; where n is selected from the values zero and one; where A is a metalloid atom of column VB (column of nitrogen) (the periodic table of elements used in the present application is that of the supplement to the Bulletin of the Chemical Society of France, January 1966, No. 1); where E is a divalent group carrying at least one conjugated double bond with the E = A double bond and / or another metalloid atom carrying at least one doublet, which is conjugated directly or indirectly with the E double bond = A, preferably a metalloid of the VB column whose doublet is conjugated directly or indirectly with the double bond E = A.

 These ionic compositions, whose cation has just been detailed, are already known to a person skilled in the art. Thus, mention may be made of the article in the Journal of Fluorine Chemistry (1999) 1-3. One can also refer to the review published in Angewandde Chemie entitled lonic Liquids - "New Solution for Transition Metal Catalysis" by Peter Wasserscheid and Wielm Keim: Angew. Chem. Int. Int. Ed., 2000, 39, 3772-3789.

According to the present invention, the co-anion (s) are advantageously chosen from anionic nucleophiles (playing the role of nucleophile in nucleophilic substitution), among the anions, advantageously monovalent, whose associated acid has an acidity at least equal to that of trifluoroacetic acid and among the

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 mixtures of anionic nucleophiles and anions, advantageously monovalent, whose associated acid has an acidity at least equal to that of trifluoroacetic acid.

During the study that led to the present invention, it was shown that these ionic liquids, when used under the same conditions (ie in the same ranges of time, temperature, pressure, anhydricity) than those of the usual solvents, allowed to be at least as effective as the usual solvents, and that under certain conditions, they allowed to obtain particularly interesting results.

 In addition to the fact that they make it possible to carry out reactions which, in ordinary times, are very difficult to carry out in nonionic solvents, these ionic solvents, or molten salts, also allow the selectivity of the exchange with extremely selectivity coefficients. high. As will be seen later, it is possible to play on the lipophilicity and the molecular weight of the cation to favor certain reactions vis-à-vis others.

 On the other hand, surprisingly in the chlorine-fluorine exchange, the preferred coanions are not those which are usually preferred.

 In particular, the anions giving the best results in the two exchanges are anions neither complex nor highly relocated.

Thus, anions PF6-, BF4-, triflic and triflimidide, although giving good results, are not the ones that give the best.

 The preferred ones are the halide anions without it being possible to give a fully satisfactory mechanistic explanation.

 Phosphoniums, where n is zero, give particularly interesting results for reactions of a Meisenheimer nature. Other cations, especially those where n is zero are much more versatile, and have the advantage of being liquid at lower temperatures, at least in general.

 When n is zero, the compound of formula G is preferably such that A is nitrogen; the possibility that it is phosphorus certainly exists, but this limits the use of the media, because of the oxidability of these compounds and their relative instability.

When n is zero, it is desirable for the divalent radical E to be such that E represents a radical DA "equal to form a compound of formula (Ia):

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 where A "is an atom of the VB column or a hydrogen-bearing carbon atom or substituted by a hydrocarbon radical R5, where the radical D is selected from - the chalcogen monosubstituted by a monovalent radical R6, (in which case the chalcogen is the said doublet-bearing metalloid), - the metalloids of column VB, in particular nitrogen or phosphorus, (in which case the metalloids of column V constitutes the said doublet bearing metalloid), preferably nitrogen, or monosubstituted by a divalent function or radical; R7, to form a radical D of formula -A '= R7, either by two monovalent hydrocarbon radicals R6, and R'6, to form a radical D of formula -A' (R6,) (R'e); the sp2 hybridization carbon atoms substituted with a hydrogen-containing R7 divalent functional group or radical or optionally substituted by a R6 carbon radical.

 It should be remembered that in this formula, when n is zero, the metalloids of column VB are preferably nitrogen, whether for A "or for A '.

When A "is a VB column atom, and especially a nitrogen atom, it is preferred that D be chosen from carbon atoms sp2 substituted by a function or by a divalent radical R7 carrying a hydrogen or optionally substituted by a carbon radical R6 to give a formula of D specified below: When said carbon carries a hydrogen, this hydrogen is found in place of R6

As has been said previously, it is desirable that the cation of formula G in which n is equal to zero comprises a metalloid atom (saturated, that is to say not carrying a double bond), having a resonance with a bond connecting two atoms, at least one of which is a disubstituted and positively charged atom of the VB column; advantageously an organic cation comprising a trivalent atom of column VB (column of nitrogen in the Mendeleyev table),

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 advantageously nitrogen, an atom whose doublet is conjugated directly or indirectly to a bond linking two atoms, at least one of which is an atom of the column VB (namely A).

 The metalloid atoms having a resonance (directly or indirectly via double bond (s), advantageously carbonecarbon) with a # bond, generally a doublet conjugated with a # bond, are advantageously chosen from those having an effect strong donor mesomer, that is to say those which, with their possible substituents, have a factor R (contribution of the resonance, see in particular the "March", third edition, table 6 of page 248) significantly negative, more precisely at most equal to -0.4, advantageously at most equal to -0.6; preferably at most equal to -1.5; more preferably at most equal to -2. When there are several metalloid atoms having the above resonance properties, it is then possible to sum said R factors, said sum then advantageously being at most equal to 0.5, preferably at -0.8, more preferably at most -2.

 Said organic cation comprising a saturated metalloid atom having a resonance with a bond n is advantageously such that said metalloid atom is a chalcogen substituted by an aromatic or aliphatic radical, or preferably a trivalent atom of the VB column, which is preferably a trisubstituted atom forming a tertiary base. The said organic cation may comprise several saturated metalloid atoms resonant with the said # bond. Which have the advantage of better relocating the positive charge.

 According to a particularly advantageous embodiment of the present invention, said bond linking two atoms is the bond of an iminium function (> C = N <).

This iminium function can be written in the following manner.

With A "representing a carbon with D selected from: - chalcogenes monosubstituted by a monovalent radical R6, - a metalloid of column VB, in particular nitrogen or phosphorus, preferably nitrogen, or monosubstituted by a function or a divalent radical R7:

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 . either by two monovalent radicals R6 and R'6; and sp2 carbon atoms substituted by a hydrogen-containing divalent R7 function or radical or optionally substituted with a carbon radical R6. with R5 chosen from hydrogen, the values of D and from hydrocarbon radicals, advantageously aryl and especially alkyl radicals.

 It is preferable that the radical D and this iminium function be arranged in such a way that the nitrogen atoms and said metalloid are as far as possible, in other words and for example that the nitrogen of the iminium function is the of the two atoms connected by the bond 71: which is the farthest from the trivalent atom of the column V. What has just been said about the iminium function is general for all the atoms of the column VB connected by the # bond, in the case where the bond% comprises a carbon atom and an atom of the column V.

Avec Q représentant un chalcogène substitué par un radical aliphatique ou aromatique Rg ; ou plus préférentiellement un azote disubstitué par deux radicaux, identiques ou différents, aliphatique ou aromatique Rg et Rio : (R10)(R9)N-; avec v égal à zéro ou un entier choisi dans l'intervalle fermé (c'est-à-dire comprenant les bornes) 1 à 4, avantageusement de 1 à 3, de préférence de 1 à 2 et où R1, R2 et R3 identiques ou différents, sont choisis parmi les dérivés hydrocarbonés, avantageusement alcoyles d'au plus 4 atomes de carbone et l'hydrogène. According to the present invention, it is preferred that the organic cation comprising a trivalent atom of the VB column whose doublet is conjugated to a # -link, has a sequence, or rather a backbone, of formula> N- [C = C] vC = N ~ <, with v equal to zero or an integer selected from the closed (i.e. including boundaries) range 1 to 4, preferably from 1 to 3, preferably from 1 to 2. Preferably the previous sequence meets the formula

With Q representing a chalcogen substituted by an aliphatic or aromatic radical Rg; or more preferably a nitrogen disubstituted by two radicals, identical or different, aliphatic or aromatic Rg and Rio: (R10) (R9) N-; with v equal to zero or an integer selected from the closed range (i.e. including the boundaries) 1 to 4, preferably 1 to 3, preferably 1 to 2 and wherein R1, R2 and R3 are the same or different, are chosen from hydrocarbon derivatives, advantageously alkyl of at most 4 carbon atoms and hydrogen.

 Advantageously, according to the present invention, said trivalent atom of the VB column forms or constitutes a tertiary amine.

 More specifically, it is desirable that said organic base comprising a trivalent atom of the VB column whose doublet is conjugated to a bond constitutes a molecule of the following formula: (R10) (R9) N- [C (R8) = C (R6 )] vC (R5) = N ± (R1) (R2)

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 with v equal to zero or an integer selected from the closed range (i.e. including the boundaries) 1 to 4, preferably 1 to 3, preferably 1 to 2 and wherein R 1, R 2, R 5, R6 and R8, which are identical or different, are chosen from hydrocarbon groups, advantageously alkyl groups of at most 4 carbon atoms, and hydrogen, and wherein R10 and Rg, which are identical or different, are chosen from hydrocarbon groups, advantageously alkyl groups of at most 4 carbon atoms, one or two of the substituents R1, R2, R5, R6. R8. Rg and R10 may be connected to other substituent (s) remaining to form one, two or more rings, including aromatic, see below.

 The delocalization effect is particularly marked when said link connecting two atoms is intracyclic (or a mesomeric form is intracyclic), especially when it is intracyclic in an aromatic ring.

This is particularly the case for pyridine, diazinic (preferably meta-diazine or infra) cycles and rings derived therefrom such as quinoline or isoquinoline such as for example:

Thus the pyridine rings, especially enriched by the presence of one or more metalloid atoms, especially when the sum of the R (see above) is at most equal to -1.5, advantageously -2, constitutes particularly satisfactory cations.

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 More specifically, the organic base comprising a saturated metalloid atom, having a resonance with a bond, may advantageously be chosen from dialkylaminopyridines, especially in the para- or ortho- position (that is to say in the 2-position of the pyridine or in formula 2). above); DBU (diazabicycloundecene) also gives an interesting cation.

 Five-membered rings are particularly interesting when they have two or three heteroatoms.

R6' et R6" ont la même valeur que R6. For example, structures of the imidazole, oxazole or cyclic guanidine or even indole type

R6 'and R6 "have the same value as R6.

 It is possible to substitute the free aryl (aromatic) or aliphatic (whose attachment point is a sp3 carbon). But this presents rather little interest and the disadvantage of weighing down the cation.

Les structures pyrazole sont également possible, mais moins satisfaisantes en raison de la moindre résonance. Triazole structures are also possible

Pyrazole structures are also possible, but less satisfactory because of the lower resonance.

It should also be mentioned that among non-cyclic structures, there may be some interest in using guanidinium structures which have the characteristic of being easily derived from guanidine and of having a strongly resonant formula.

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Where R6 "" and R6 "" are selected from the same values as R6, they may be the same as or different from the other R6s, as well as R1 and R2. It is preferable if low melting compounds are desired that the molecule be asymmetric.

R6 "and R6" "can be connected together to form rings, preferably aromatic.

 According to the present invention, it is advantageous to choose cations and quantities of cations such that there is a concentration of cation (s) according to formula G at least equal to 2 moles per liter or more exactly two equivalents of cationic per liter, preferably 3 equivalents and even 4 equivalents per liter. The higher the value of this concentration, the better the yields, but not necessarily the selectivity.

For compounds of formula G where n is zero, it is desirable that the molecular weight of the cation is at most 300, preferably 250, more preferably 200. When the cations are polyvalent (i.e. say, carry several positive charges), these values must be reduced per unit charge; in other words, a divalent cation may be of higher molecular weight than twice the masses set out above.

 To avoid too much crystallinity and to lower the melting point, it is preferable that the compounds of formula G according to the invention have a molecular mass of at least 100. It is preferable that the reaction medium consisting mainly of the ionic solvent is as dry as possible. However, because of the high hygroscopicity of the cations according to the present invention, it is advisable to dehydrate these reaction media before use. The reaction medium before use is advantageously such that a mass ratio between the salt whose cation corresponds to formula G and the water is at most equal to 200 ppm, preferably 100 ppm (in this ratio, the numerator is constituted by water, of course). A good way to dehydrate is to heat under vacuum for 2 hours, preferably 8 hours under vacuum at 70 ° C., the vacuum being the vacuum of the paddle pump, ie 10 -2 mm of mercury.

 Advantageously, said reaction medium is aprotic and anhydrous. In particular it is desirable anhydrous is such that the strongest acid present in the medium, excluding the substrate has a pKa at least equal to.

 The protons derived from acid (s) whose pKa is less than the value of 25, advantageously 30, preferably 35, are known as labile hydrogen.

 The more aprotic the medium is, that is to say that its content of releasable protons in the reagent will be low, the less there will be a risk of parasitic reaction and the better the yield.

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 Thus, it is preferable that, in the composition according to the present invention, serving as a reagent or a reaction medium, the content of labile hydrogen atoms, such as the ratio between the amount of labile hydrogen equivalent (numerator) and the amount of cation of formula G expressed in equivalent. at most equal to 1%, advantageously 1 per thousand, preferably 1000 ppm (in moles, or equivalent when the species considered are polyfunctional).

 This effect is particularly important when the reaction is conducted at a temperature greater than about 240 K (in the present description the term "about" is used to emphasize the fact that, when the rightmost digit (s) of 'a number are zeros, these zeros are position zeros and not significant digits, except of course if it is otherwise specified.

 It is interesting, especially when the cation has less than 7 carbon atoms in the cation structure, to avoid any symmetry, which is likely to facilitate crystallization. Thus, the substituents of the nitrogen (more generally A and A 'or even A ") are preferably of different size.

 The radicals R 1 to R 10 are chosen in such a way that none of the atoms of the nitrogen column and any of the chalcogens carry a hydrogen with this proviso: the radicals R 1 to R 10 which can be independently identical or different are advantageously chosen from alkyls and aryls. In addition, R 5 and R 8 may be aryloxyl, alkyloxy, amino groups substituted by two alkyls, by two aryls or by alkyl and aryl. R6, when carried by a carbon, may also be dimethylamino, aryloxyl or alkyloxy.

Thus, R 5 can be chosen from hydrogen, the values of D and from hydrocarbon radicals, advantageously aryl and especially alkyl radicals.

 Provided that it is not carried by a chalcogen or an atom of column VB, they can also be hydrogen as R5, R6 and R8.

 The total number of carbons when n is zero in the formula G is advantageously at most equal to 30, preferably at most 20, more preferably at most 15. It is desirable that at most two, and even preferably at most only one hydrocarbon group, when they are, R1, R2, R5, R6, R8, R9 and R10 have a carbon number greater than 6.

 To facilitate the treatment of the reaction mixtures, it is preferable that the cation of formula G is stable in the presence of water and that it is not miscible in any proportion.

 The term alkyl is taken in its etymological sense from the rest of an alcohol from which the OH function has been removed. Thus, it covers in particular the radicals whose free bond is carried by a sp3 hybridization carbon atom, which atom of

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 carbon is only bound to carbons or hydrogens. In the case of the present invention, among the alkyls, it is appropriate to mention, in addition to the radicals of formula CnH2n + i, those derived therefrom by substitution with atoms and / or functions (it is preferable to avoid parasitic reactions by selecting functions which are inert under the conditions of implementation of the invention) and in particular those which carry ether functions and in particular mono-, oligo-, poly- or poly-ethoxylated chains derived from the epoxides of alkene and especially ethylene. Finally, as we have seen previously, the radicals R1 to R10 can be linked together to form rings, and especially aromatic heterocycles.

 Imidazoliniums give particularly interesting results, in particular as regards the chlorine and fluorine exchanges on sp3 hybridization carbons. The imidazoliniums giving the best results are those where R5 is hydrogen and where R1 and R6 are alkyl while not having the same chain length. The preferred and most active chain lengths are those which are such that when R 1 is methyl and R 6 is between methyl and butyl. Tests where the chain length of R6 is 8 carbon atoms are less efficient but show high selectivity.

 The preferred imidazoliniums are those which have at most twelve, preferably at most ten, carbon atoms.

 With regard to the substrates, the substrate for the exchange on aliphatic carbons is advantageously a substrate comprising a spon hybridization halogenophore carbon bearing at least two halogens, at least one of which is a halogen of atomic number greater than that of the halogen atom. fluorine, the other two substituents of the carbon may be two alkyls, a chalcogen atom or another halogen atom bearing a doublet, or an aryl and an alkyl, or two aryls. However, it has been shown that the reaction worked all the better that firstly said halophoric carbon did not carry hydrogen, secondly that it bore either a chalcogen likely to provide a doublet in good conditions, that is to say say a chalcogen in the oxidation state minus two, usually an ether or an ester, or their equivalent in which the oxygen is replaced by a sulfur.

 Another series of compounds giving good results is the case where the halophoric carbon is connected to at least one weak hybridization atom carrying an acidic unsaturation. In addition to the case where said weak hybridization atom carrying an unsaturation is engaged in a carbon-carbon bond (acetylenic, preferably ethylenic, which ethylenic bond is advantageously engaged in an aromatic cycle), it may be indicated that

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teaching by the example that, advantageously, said weak hybridization atom carrying an unsaturation is an atom engaged in one of the double bonds [where * C is the halophoric carbon] following: atom of low degree of facility of the exchange the hybridization reaction and (easy = 1, easy = 2 but more unsaturation of which it is selective, relatively difficult = 3) carrier - * C-CR "= NR '2 - * C-CR" = S' 1 - * CC = N-NH-R '2 - * C-CR "= N-O-R' 2 - * C-CR" = PR '2 - * CN = NR' 2 sometimes fragile compounds which limits the field of the operating conditions acceptable - * C-CF = CF2 2 polymerization risk - * C-CR = "O 3 Difficult reaction - * CN = O 2 can give rise to very complex mixtures
Thus, the general formula of the substrate can be written in the following manner.

Pour former le substrat de formule

Where R is selected from hydrocarbon residues (ie containing carbon and hydrogen, especially aryl or alkyl), halogens, electron-withdrawing groups (preferably by inducing effect), with X chosen from halogens, preferably chlorine, with X 'chosen from halogens, preferably chlorine, with, of course, the proviso that R, X and X' can not simultaneously be fluorine, and that X one of them represents at least one heavier halogen than fluorine to be exchanged with fluorine, preferably chlorine, with X "chosen from aryls, halogens, alkyloxy, thioalkyloxy, acylalkyloxy, thioacylalkyloxy, aryls and alkyls as well as by a radical of formula below:

To form the substrate of formula

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 Z is selected from the trivalent metalloids with r equal to zero or tetravalent with r equal to 1 (respectively phosphorus and advantageously nitrogen on the one hand and carbon on the other hand, preferably carbon); and Z 'is selected from metalloids preferably chalcogen (with s and t equal to zero), nitrogen and phosphorus (with s equal to zero) and carbon with s and equal t); r, s, and t can be zero or one, as represented by Z and Z '.

Surprisingly R can be hydrogen and give rise to easy exchange especially when the compound is of formula two, preferably when Ar is homocylic.

R can also be of the type -Z (R10) r = Z '(R11) s- (R5) t Y inclusive of Ar (Rn) s type. to give or not a symmetrical molecule.

R15 can be hydrogen or any radical, preferably hydrocarbon (that is to say containing carbon and hydrogen).

R 2 can independently take the same values as R 15 R 11 can independently take the same values as R 15 however according to the present invention R 12 and R 15 are advantageously joined to form an aromatic ring, which amounts to the case where X "is aromatic.

 According to the present invention, it is preferable that R, X 'and X are such that there are at least two halogens distinct from fluorine and that there is at least one halogen which is chlorine.

 It is also preferable that R and X "are such that one of them is aromatic, halogenous, advantageously distinct from fluorine, a radical linked by a chalcogen to the halophoric carbon (that is to say carrying X and X or a radical carrying a double bond, such that the halophoric carbon is in position.

 As has been shown previously, the halogen-fluorine exchange reactions, preferably and most often chlorine-fluorine, are particularly selective in the case where in the general formula n is equal to one. To obtain the selectivity, it suffices either to limit the amount of the nucleophile, in general fluoride, or to limit the temperature, or to limit the duration. As can be seen in the examples, this selectivity of exchanges is particularly impressive.

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 The nucleophiles are those which have already been mentioned in the body of the present description, in particular the anionic or even neutral nucleophiles, whose pKa of the associated acid is at most equal to 4 when the nucleophile is a fluoride, the fluorides may be introduced in the form of alkaline fluoride, preferably alkaline fluoride whose alkali metal is greater than or equal to that of sodium, preferably at least equal to that of potassium. The fluoride ions may also be introduced in the form of the coanion of the compound of formula G or may finally be introduced in the form of ammonium or phosphonium.

 As has been seen previously, the coanions are preferably coanions corresponding to very strong acids, especially those whose Hammett constant is greater than or equal to that of trifluoroacetic acid.

 However, as already mentioned, one can use on the one hand as coanion anionic nucleophiles that will act on the substrate.

 However, as already mentioned, it has been shown that the most common coanions for ionic liquids, namely complex anions such as BF4., And PF6- give results which, to be good, are not the same. best. The same applies to anions of the perfluoroalkanesulfonic type and the corresponding imides such as triflimide.

 As the perfluoroalkanesulfonic acid, it is appropriate to mention the sulphonic acids carrying a difluorinated carbon, the rest of the molecule being indifferent, provided that it does not react.

 The preferred anions are the anions corresponding to the heavy halides (iodide, chloride and bromide) and more particularly to chlorides and bromides. For exchange by SN2 on a sp3 carbon bearing at least two halogens including at least one chlorine, bromide is the preferred.

 In the case of the chlorine-fluorine exchange on an aliphatic carbon (that is to say of sp3 hybridization), the bromides are those which gave the best results, with the exception of the fluorides which play at the same time the role of nucleophiles and coanions.

 In any case, the presence of the bromide ion in the exchanges on aliphatic carbons is eminently profitable. Its role begins to be felt and become significant when its molar ratio between the bromide and the cation of formula G is at least equal to 5%, preferably to 10%.

 The operating conditions are substantially the same as those employing a conventional polar aprotic solvent, such as sulfolane. It is however possible to lower the temperature somewhat because of the high reactivity of the reaction medium according to the present invention.

 It is interesting to note that it is preferable, among the compounds of the formula G1 family, to use those which are immiscible with water in any

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 proportion, which facilitates the purification of these compounds of formula G1 which, remember, are in principle not distillable.

 The following examples illustrate the invention.

I. SNAr exchange
In a 5 ml flask surmounted by a wheel cooler, 3 equivalents of KF and 0.4 equivalents of tetramethylammonium chloride are added in an ionic solvent, namely methylbutylimidazolinium, that is to say, where R1 is methyl. and / or R6 is butyl. The coanion is the PF6-. The whole is dried at 100 ° C. under vacuum from the paddle pump (10 -2 mm Hg) and with magnetic stirring for 3 h. One equivalent of the substrate is added and the mixture is heated for 24 hours at 150.degree.

Then, it is cooled to ambient temperature and the reaction medium is then extracted three times with 3 ml of ethyl ether. This solution is assayed by vapor phase chromatography, and NMR is monitored on the isotope 19 of the fluorine to identify the products of the reaction.

Example 1 Parachloronitrobenzene Substrate
The manipulation was carried out on, on the one hand, commercial potassium fluoride, and on the other hand, on ultrafast KF obtained by atomization with more than 300 of an aqueous solution of potassium fluoride. In the case of commercial fluoride, 60% of the fluorinated product and 40% of the starting material are obtained in the same uses of atomized potassium fluoride slightly improve the results.

Example 2 Action on trichloronitrobenzene
The general procedure is repeated by changing the amounts of KF and tetramethylammonium chloride, 2 equivalents of KF, 1 equivalent of tetramethylammonium chloride are used here, 18% of the starting product, 35% of the ortho-substituted mono, are recovered. 6% of substituted mono in para and 31% of difluorinated. Comparisons by lowering the proportion of phase transfer agent show that it is relatively unimportant.

EXAMPLE 3 Comparison between Different Ionic Solvents The comparison is made between: # butylmethylimidazolinium, hereinafter referred to as Bmim with coanion
PF6-;

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linear C8 N-octylmethylimidazolinium, this cation will be designated later by Csmim with BF4 as coanion; # the butyldimethylimidazolinium hereinafter referred to as Bdim with coanion
BF4; ethylmethylimidazolinium, hereinafter referred to as Emim and in the form of bromide; # and sulfolane which represents the prior state of the art.

It should be noted that when there are two substituents on imidazole, these two substituents are located on each of the nitrogens. When there is a third substituent, it is substituted on the carbon located between the two nitrogens, and corresponds in the nomenclature of the present description to R5.

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 EmimBr M.P. 79-81 C; soluble in water, soluble in CH2Cl2, insoluble in Et2O.

Comparison with BmimPF6. C8mimBF4, BdmimPF6 and sulfolane.

CCI 92 CF2CI CF3 CCI3 63 KFrh (2 éq.) 6""" 6""" 6 6""" Autres 1 -& 150 C J i après 20 min. CCb KF, h. (2 eq.) CFCI2 CF2CI CF3 CCI3 63 KFrh. (2 eq.) 6 6 6 6 Other U 6h., 150 C 1 1 BmimPF6 94% 5% 0% 0% 1% BdimPF6 38% 7% 0% 35% 20 % C8mimBF4 82% 3% 0% 2% 13% EmimBr 21% 63% 5% 0% 11% sulfolane 8% 5% 0% 86% 1% (by CPV)
The much higher reactivity in the EmimBr solvent is even better illustrated with the following comparison:

CCI 92 CF2CI CF3 CCI3 63 KFrh (2 eq.) 6 """6""" 6 6 """Other 1 - & 150 CJ i after 20 min.

BmimPF6 10% 0% 0% 90% 0% EmimBr 62% 17% 0% 1% 20% (by CPV) Example 4 Selectivity with respect to the monofluorinated compound

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It was a question of knowing if the most effective solvent from the point of view of the kinetics could make it possible to obtain a good selectivity to obtain a monofluorinated compound and this in particular by using a reduced quantity of potassium fluoride.

CCI CFCI2 CF2CI CF3 CCI3 JL KFrh(1éq.) I I / Il I j Autres 150 C KJ KJ 1 KJ Après 70 min BmimPF6 35% 2% 0% 62% 1 % Aprés 5 min. EmimBr 41% 2% 0% 34% 23% Après 20 min. EmimBr 54% 2% 0% 26% 18% Après 300min. EmimBr 42% 8% 0% 24% 26% (par CPV)
Comme dans le solvant BmimPF6, avec 1 équivalent de KF. la réaction bloque. Reaction with 1 single KF equivalent

CCI CFCI2 CF2CI CF3 CCI3 JL KFrh (1 eq.) II / II I j Others 150 C KJ KJ 1 KJ After 70 min BmimPF6 35% 2% 0% 62% 1% After 5 min. EmimBr 41% 2% 0% 34% 23% After 20 min. EmimBr 54% 2% 0% 26% 18% After 300min. EmimBr 42% 8% 0% 24% 26% (by CPV)
As in the solvent BmimPF6, with 1 equivalent of KF. the reaction blocks.

 For EmimBr the maximum is reached after 20 min .; after 6 hours of reaction it is found that the consumption of trichlorotoluene has changed little. Compared to the solvent BmimPF6 it is found that the consumption of the starting material is significantly higher.

- Influence of the temperature.

CCI KFrh (2 eq.) CFCI2 CF2CI CF3 CCI3 Other 1 120 C 1 After 300 min BmimPFe 2% 0% 0% 97% 1% After 90 min. EmimBr 78% 3% 0% 14% 5% (by CPV)

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CCI CFCI2 CF2CI CF3 CCI3 6KFrh (Séq.) 6 6 6 6 Autres 1 h 150 C h h 1 h h Après 10 min EmimBr 30% 57% 4% 1% 8% Après 200 min. EmimBr 4% 77% 12% 0% 7% (par CPV)
Au vu de ces résultats, on s'aperçoit qu'il est possible d'accéder sélectivement aux composés monofluorés et difluorés. L'accès au composé trifluoré est également possible. Example 5 Synthesis of the difluorinated compound

CCI CFCI2 CF2CI CF3 CCI3 6KFrh (Seq.) 6 6 6 6 Other 1 h 150 C hh 1 hh After 10 min EmimBr 30% 57% 4% 1% 8% After 200 min. EmimBr 4% 77% 12% 0% 7% (by CPV)
In view of these results, it can be seen that it is possible to selectively access monofluorinated and difluorinated compounds. Access to the trifluorinated compound is also possible.

We notice that for the fluorination reaction studied we can determine at this stage 3 types of solvents: - Very reactive solvent: EmimBr - Solvent reagent: EmimPF6> BmimPF6, BmimBF4> C8mimPF6, C8mimBF4 - Solvent a little less reactive: BmimCI, BmimTf2N
The anion and the length of the alkyl chain have an influence on the result.

 By lengthening the alkyl chain (increase in hydrophobicity) the reactivity is decreased.

Example 6 Properties of different imidazoliniums tested

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<tb> Solubility <SEP> Stability
<tb> viscosity <SEP> (cP) <SEP> density <SEP> (kg / 1) <SEP> water <SEP> CH2CI2 <SEP> EtOAc <SEP> Et2O <SEP> toluene <SEP> P. <SEP> F. <SEP> air <SEP> thermal
<tb> n = 2 <SEP> 37.7 <SEP> (295 <SEP> K) <SEP> 1.24 <SEP> (295 <SE> K) <SEP> s <SEP> s <SEP> 12 <SEP> C <SEP> Hygroscopic <SEP> 300 <SEP> C
<tb> CnMIMBF4 <SEP> n = 4 <SEP> 233 <SEP> (303 <SEP> K) <SEP> 1.17 <SEP> (293 <SEP> K) <SEP> s <SEP> s <SEP > (-) <SEP> 78 <SEP> C <SEP> Hygroscopic <SEP> 300 <SEP> C
<tb> n = 6 <SEP> ins <SEP> s <SEP> (-) 82 C <SEP> hygroscopic
<tb> n = 8 <SEP> ins <SEP> s <SEP> (-) 79 C <SEP> hygroscopic
<tb> n = 2 <SEP> ins <SEP> 62 <SEP> C <SEP> hygroscopic
<tb> CnMIMPF6 <SEP> n = 4 <SEP> 312 <SEP> (303 <SEP> K) <SEP> 1.37 <SEP> (303 <SEP> K) <SEP> ins <SEP> s <SEP > s <SEP> ins <SEP> ins <SEP> (-) <SEP> 61 <SEP> C <SEP> hygroscopic
<tb> n = 6 <SEP> ins
<tb> n = 8 <SEP> ins
<tb> n = 2 <SEP> s <SEP> ~~~~ <SEP> 87 C
<tb> CnMIMCI <SEP> n = 4 <SEP> s <SEP> ins <SEP> 65-69 <SEP> C <SEP>
<tb> n = 6s
<tb> CnMIMCF3SO3 <SEP> n = 2 <SEP> 4, <SEP> 9 <SEP> (298 <SEP> K) <SEP> 1.39 <SEP> (298 <SE> K) <SE> s <SEP> s <SEP> s <SEP> ins <SEP> (-) <SEP> 9 <SEP> C
<tb> n = 4 <SEP> 90 <SEP> (293 <SEP> K) <SEP> 1.29 <SEP> (293 <SEP> K) <SEP> s <SEP> s <SEP> s <SEP > ins <SEP> 16 <SEP> C <SEP> ~~~~~~~~~~~
<tb> CnMIM (CF3SO2) N <SEP> n = 2 <SEP> 34 <SEP> (293 <SEP> K) <SEP> 1.52 <SEP> (295 <SEP> K) <SEP> ins <SEP > s <SEP> s <SEP> ins <SEP> (-) <SEP> 3 <SEP> C <SEP>><SEP> 400 <SEP> C
<tb> n = 4 <SEP> 52 <SEP> (293 <SEP> K) <SEP> 1,429 <SEP> (292 <SEP> K) <SEP> ins <SEP> s <SEP> s <SEP> ins <SEP> (-) <SEP> 4 <SEP> C <SEP> ~~~~ <SEP> ~~~~~
<Tb>
s = soluble ins = insoluble

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EXAMPLE 7 Study of Different Ionic Solvents in the Monofluorination of Phenyl Chloroform

Preparation of ionic solvents Example 7a Preparation of ionic solvents
Various procedures have been described in the literature for the synthesis of ionic solvents. With regard to the ionic solvents having an imidazole cation, the synthesis starts with the formation of the halide, by condensation of imidazole and the corresponding haloalkane (Scheme 2).

Figure 2
The second part of the synthesis consists of exchanging the chloride ion with the desired anion; 3 methods have been described in the literature: - by reaction with the corresponding acid (eg HPF6);
Problem: presence of acid in the final ionic solvent.

by reaction with the corresponding sodium salt (eg NaBF 4);
Problem: the reaction is often incomplete and CnmimCI is miscible in
CnmimA.

by reaction with the corresponding silver salt (ex: Ag BF4)
Problem: this method is limited by the price of the silver salts used (ex: AgBF4 5g / 514 frs Aldrich).

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 The method using the acid solution has the advantage of being a complete reaction and traces of acids can be eliminated if care is taken to wash the ionic solvent formed with water until neutral pH. If the solvent is stored for a long time, it is useful to rewash it with water before use.

 It has been shown that a filtration on silica gel and a washing with sodium carbonate makes it possible to reach a better purity, in particular in the case where the anion exchange reaction was made using the sodium salt .

 For our study we synthesized our solvents using anion exchange with an acidic solution of HPF6 or HBF4 as described below.

Procedure for bmimPF6 (1-n-butyl-3-methylimidazolinium hexafluorophosphate)
1-methyl-1H-imidazole (15 ml, 0.18 mmol) and 1-chlorobutane (19 ml, 0.18 mmol) were stirred at 70 ° C. under reflux for 72 hours. The resulting liquid was allowed to cool to room temperature and then washed with ethyl acetate (3 x 50 ml). Residual traces of ethyl acetate were removed by vacuum drawing followed by dilution of the viscous liquid in water (100 ml).

Hexafluorophosphoric acid (30 ml of a 60% solution in water, 0.2 mol) was added to the resulting emulsion carefully to avoid violent release of temperature, then the mixture was stirred all the time. night.

The two phases were separated and the ionic liquid was washed with aliquots of water (30 ml) until this wash water was no longer acidic. The mixture was then heated under vacuum at 70 ° C to remove traces of water and obtain the ionic liquid BmimPF6 (47 g, 92% yield). Finally, a passage over silica gel of the ionic liquid BmimPF6 dissolved in dichloromethane (50 ml) followed by several washes of the silica gel with dichloromethane (5 x 20 ml) made it possible to obtain colorless BmimPF6 (39 g, 76 g). % yield).

 The other ionic solvents CamimBF4 and BdimPF6 were prepared following this method using the corresponding starting products. All were analyzed by NMR of fluorine, proton, carbon and phosphorus (for PF6 anions).

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CCI3 KF,. (2 éq.) ÇFCI2 ci CCI3 f!! bmimPF6 - r') ri r! autres bmimPF6 autres 6h., 150 C 1 mmol 94% 5% 0% 1% (par CPV) 10 mmol 94% 5% 0% 1 % (par CPV)
Schéma 3 La réaction de monofluoration est totale en utilisant 2 équivalents de fluorure de potassium, après 6h. à 150 C. En début de réaction, le solvant ionique se colore en rouge, et cette coloration persiste même après lavage à l'eau et à l'éther mais la RMN du proton indique que le solvant est propre. Example 7b Reactivity of the Various Ionic Solvents - In BmimPF6

CCI3 KF ,. (2 eq.) ÇFCI2 ci CCI3 f !! bmimPF6 - r ') ri r! other bmimPF6 other 6h., 150 C 1 mmol 94% 5% 0% 1% (by CPV) 10 mmol 94% 5% 0% 1% (by CPV)
Scheme 3 The monofluorination reaction is total using 2 equivalents of potassium fluoride, after 6h. at 150 C. At the beginning of the reaction, the ionic solvent turns red, and this coloration persists even after washing with water and with ether, but the proton NMR indicates that the solvent is clean.

Catalyst Influence Tetramethylammonium chloride has been used in preliminary studies to catalyze this reaction. However, under the conditions described here, for the monofluorination reaction, the catalyst has no influence on the kinetics of the reaction as can be seen by comparing the curves of FIG.

Influence of the amount of KF The curves of FIG. III show that, with 1.5 equivalents of KFrh, the reaction slows down: 70% of PhCFCl2 and 30% of PhCCI3.

The curves in FIG. IV show that, under the same conditions, with 1 equivalent of KFrh, the reaction slows down: 34% of PhCFCl2 and 66% of PhCCI3.

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EXAMPLE 8 Recycling of the BmimPF6 Solvent The procedure used for each reaction is as follows:
A suspension of 116 mg (2 mmol) of potassium fluoride in 2 ml of butylimidazolinium hexafluorophosphate was stirred for 1 h at 100 ° C. under a vacuum of 0.1 mm Hg.

 After replacing the vacuum with nitrogen, it is heated to 150 ° C., then 142 μl of phenylchloroform (1 mmol) are added, and the reaction mixture is heated at 150 ° C. for 6 hours. The organics were extracted three times with 3 ml of diethyl ether. The ionic liquid was washed three times with 3 ml of cold water. The ionic liquid was then heated again at 100 ° C for 1 h under vacuum before reuse as before.

Claims (10)

 where R 1, R 2, R 3, and R 4, which are identical or different, are chosen from monovalent hydrocarbon radicals; where n is selected from the values zero and one; where A is a metalloid atom of column VB (column of nitrogen) (the periodic table of elements used in the present application is that of the supplement to the Bulletin of the Chemical Society of France, January 1966, No. 1); where E is a divalent group carrying at least one conjugated double bond with the E = A double bond and / or another metalloid atom carrying at least one doublet, which is conjugated directly or indirectly with the E double bond = A, preferably a metalloid of the VB column whose doublet is conjugated directly or indirectly with the double bond E = A.

 1. A composition useful as a reaction medium characterized in that it comprises at least one ionic compound whose cation is of general formula G: 2. Composition according to claim 1, characterized in that it comprises as co-anion an anion selected from halides and mixtures thereof. 3. Composition according to one of claims 1 and 2, characterized in that it further comprises an anionic nucleophile whose pKa of the associated acid is at most equal to 5, advantageously to 4. 4. Composition according to one of claims 2 and 3, characterized in that it comprises fluoride ions. <Desc / Clms Page number 32> 5. Composition according to one of claims 2 to 4, characterized in that the sum of bromide ions and chloride ions is at least equal to the amount of cation of formula G (expressed in equivalent). 6. Composition according to one of claims 1 to 5, characterized in that it is aprotic and in that it has a mass ratio between water and salt whose cation meets the formula G at most equal at 200 ppm, preferably at 100 ppm. 7. Use of the compositions according to one of claims 1 to 6 to perform a reaction of SNAr. 8. Use of the compositions according to one of claims 1 to 6 to carry out an SN2 reaction whose nucleophile is an anion whose pKa of the associated acid is at most equal to 5, advantageously to 4. 9. Use according to claim 8, characterized in that the substrate is a carrier molecule of a carbon atom sp3 itself carrying two halogens, at least one is a leaving group. 10. Use according to one of claims 8 and 9, characterized in that the nucleophile is a fluoride.